Uncontrolled Ascites Research Articles

COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls.

Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy. Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database. In the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT. Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Phase 1 study to evaluate safety and preliminary efficacy of padeliporfin vascular targeted photodynamic therapy (VTP) in patients with locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC).

TPS4204 Background: Pancreatic cancer is the third most common cause of cancer death. Surgery offers the best survival rates however only a minority of patients are eligible. Approximately 15-20% of patients are deemed unresectable due to vascular involvement LA. Conversion of unresectable tumors, due to vascular involvement to resectable, is an unmet clinical need. Methods: A novel approach was developed to destroy the tumor encasing the artery combining padeliporfin, a photosensitive drug, locally activated by laser light illumination. The effectiveness of the strategy was confirmed in an orthotopic mouse model. A proof-of-concept study using 12 non-tumor pigs demonstrated an acceptable safety profile. A phase I dose escalation trial (NCT5918783) will be performed to evaluate the safety and maximal tolerated dose (MTD) of laser light dose of padeliporfin VTP. VTP will be delivered through an endovascular fiber integrated in a standard angioplasty balloon. The balloon will be advanced under fluoroscopy to the encased vascular segment of the superior mesenteric artery (SMA) and inflated. Following IV administration of padeliporfin, it will be activated by the laser light. Part A will be a classic 3+3 dose-escalation design to determine the MTD of laser light. The identified MTD will be applied in the Part B for preliminary efficacy evaluation. The primary objectives are to determine safety and MTD and/or recommended phase 2 laser light dose of VTP treatment. Secondary objectives are: rate of surgical conversion; evaluation of the pattern of disease progression (local regional and/or metastatic disease) after VTP based on CT. Standard of care surgery can be performed after 14 days post VTP. Key inclusion criteria: patients with histologically/cytologically confirmed stage III unresectable LA-PDAC in the head/uncinate process of the pancreas, with SMA solid tumor contact ˃180° with measurable disease per RECIST 1.1 and ECOG 0-1. Key exclusion criteria: metastatic disease, other malignancy, photosensitive skin diseases or porphyria, concurrent investigational therapy within past 30 days, medically uncontrolled moderate or severe ascites, previous radiation to pancreas, SMA variants. Recruitment begins in April 2024. Conversion of unresectable locally advanced pancreatic cancer to surgery is a critical unmet need. This phase I trial explores a novel approach to treat the tumor encasement enabling surgery. Clinical trial information: NCT5918783 .

Benefit of living donor liver transplantation in graft survival for extremely high model for end-stage liver disease score ≥35.

Living liver donation with high model for end-stage liver disease (MELD) score was discouraged despite organ shortage. This study aimed to compare graft survival between living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) recipients with extremely high-MELD (score of ≥35). Between 2008 and 2018, 359 patients who underwent liver transplantation with a MELD score ≥35 were enrolled. We compared graft survival between LDLT and DDLT after propensity score matching (PSM) and performed subgroup analysis according to donor type. After PSM, there was no statistical difference in graft survival between the LDLT and DDLT groups (p = .466). Old age, acute on chronic liver failure, re-transplantation, preoperative intensive care unit stay and red blood cell (RBC) transfusion during the operation were risk factors for graft failure (p = .046, .005, .032, .015 and .001, respectively). Biliary complications were more common in the LDLT group (p = .021), while viral infection, postoperative uncontrolled ascites, and postoperative hemodialysis were more common in the DDLT group (p = .002, .018, and .027, respectively). In the LDLT group, acute chronic liver failure, intraoperative RBC transfusion, and early postoperative complications were risk factors for graft failure (p = .007, <.001, and .001, respectively). Our study showed that LDLT is not inferior to DDLT in graft survival if appropriate risk evaluation is performed in cases of extremely high-MELD scores. This result will help overcome organ shortages in high-MELD liver transplantation.

Liver Only Living Donor Transplantation for Polycystic Disease in a Patient on Chronic Hemodialysis: Case Report

Polycystic liver disease (PLD) is characterized by the progressive development of polycystic lesions in the kidney and the liver, possibly resulting in dual organ failure. We indicated living donor liver transplantation (LDLT) for a patient with end-stage liver and kidney disease (ELKD) due to PLD on uncomplicated chronic hemodialysis. A 63-year-old man with ELKD and uncontrolled massive ascites due to PLD and hepatitis B on uncomplicated chronic hemodialysis was referred to us with a single possible 47-year-old female living donor. Because of the necessity of right lobe liver procurement from this small middle-aged donor and uncomplicated hemodialysis on this recipient, we considered LDLT, rather than dual organ transplantation, could be the most well-balanced option to save the life of this recipient with acceptable risk limits for this donor. A right lobe graft with 0.91 for graft recipient weight ratio was implanted with an uneventful operative procedure under intra- and postoperative continuous hemodiafiltration. The recipient was rescheduled on routine hemodialysis on day 6 after transplantation and recovered with a gradual decrease in ascites output. He was discharged on day 56. He continues to have a very good liver function and quality of life without ascites and uncomplicated routine hemodialysis 1 year after transplantation. The living donor was discharged 3 weeks after surgery and is also doing well. Although combined liver-kidney transplantation from a deceased donor could be the best option for ELKD due to PLD, LDLT can also be an acceptable option for ELKD with uncomplicated hemodialysis, considering the double equipoise theory for both lifesaving of the recipient and acceptable donor risk.

A phase I clinical trial of stereotactic body radiotherapy with atezolizumab and bevacizumab in advanced hepatocellular carcinoma.

TPS626 Background: Systemic therapy with atezolizumab and bevacizumab (atezo/bev) has improved outcomes for advanced HCC, but results in objective responses in fewer than 30% of patients. Stereotactic body radiotherapy (SBRT) is currently used for small HCC tumors that do not require systemic therapy but has also been shown in a number of clinical trials of other solid tumors to enhance the anti-cancer immune response. Of particular interest, our prior experience with SBRT in a 17Gy fraction has demonstrated the ability to restore sensitivity to immunotherapy in advanced solid tumors, even those previously refractory to immunotherapy. We hypothesize that repeated high dose fractions of radiation will act as an immune booster and will improve on outcomes of patients with advanced HCC. Since the combination of SBRT and atezo/bev has not yet been tested prospectively in patients with HCC, and because bevacizumab is a known radiosensitizer, we are conducting a phase I trial to evaluate the safety of repeated SBRT doses. Methods: This is a single-site phase I clinical trial utilizing a Rolling 6 design to determine the safety of 1, 2, or 3 doses of SBRT fractions in combination with atezo/bev. Up to 18 total patients will be enrolled (n=6 per cohort). Patients must be naïve to systemic therapy with Child-Pugh A or B liver function, at least one lesion amenable to radiation, and a measurable lesion that will not receive radiation. Patients with uncontrolled ascites or hepatic encephalopathy are excluded. Atezo/bev is administered at the standard doses every 21 days. SBRT will start 1 week after the first infusion of this combination. Patients will receive 1, 2, or 3 17Gy fractions of SBRT at 4-week intervals (cohorts 2 and 3 only). Patients will undergo serial collections of circulating cell-free DNA (ccfDNA), methylated DNA, and peripheral blood mononuclear cells to investigate the application of these markers as a predictor of response. Following completion of SBRT, patients will continue with atezo/bev until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the proportion of patients experiencing dose-limiting toxicities (grade 3 or higher radiation-related toxicities graded by the Common Terminology Criteria for Adverse Events, Version 5). Secondary endpoints are overall survival, progression-free survival, objective response rate, duration of response, and toxicity rates. Enrollment began 9/2022 and complete accrual is expected by June 2024. NCT05488522. Clinical trial information: NCT05488522 .

A crying liver: a scan pattern mimicking spontaneous perforation of the biliary ducts.

A 2-month-old infant was referred for hepatobiliary scintigraphy due to ascites of unknown cause. The top differential diagnosis was spontaneous perforation of the biliary ducts. Delayed images up to 4 hours were against this diagnosis showing normal distribution of the radiotracer throughout the bowel. However, on delayed images, the scan showed mild tracer retention in the ascites confirmed by SPECT/CT images. Surprisingly, the exploratory abdominal surgery revealed an intact hepatobiliary system, pointing toward other possible etiologies. Second-review surgery was performed due to uncontrolled progressive ascites showing congestive hepatopathy and biliary leak from the hepatic surface suggestive of the "crying liver".

Massive Hemobilia Due to Arteriobiliary Fistula after the Transjugular Intrahepatic Portosystemic Shunt (TIPS): A Case Report

The transjugular intrahepatic portosystemic shunt (TIPS) is an effective method for the treatment of uncontrolled refractory ascites, pleural effusion, and variceal bleeding, but the risk of complications related to the procedure is high. Arteriobiliary fistula, which is manifested as hemobilia, is one of the major fatal complications of the TIPS. Most of the TIPS-related bleeding is a complication that occurs mainly during the portal vein puncture. We are reporting a case of massive hemobilia due to hepatic arteriobiliary fistula caused by TIPS procedure.

Umbilical hernia repair in patients with cirrhosis: who, when and how to treat.

Hernia management in patients with cirrhosis is a challenging problem, where indication, timing and type of surgery have been a subject of debate. Given the high risk of morbidity and mortality following surgery, together with increased risk of recurrence, a wait and see approach was often advocated in the past. The purpose of this review was to provide an overview of crucial elements in the treatment of patients with cirrhosis and umbilical hernia. Perioperative ascites control is regarded as the major factor in timing of hernia repair and is considered the most important factor governing outcome. This can be accomplished by either medical treatment, ascites drainage prior to surgery or reduction of portal hypertension by means of a transjugular intrahepatic portosystemic shunt (TIPS). The high incidence of perioperative complications and inferior outcomes of emergency surgery strongly favor elective surgery, instead of a "wait and see" approach, allowing for adequate patient selection, scheduled timing of elective surgery and dedicated perioperative care. The Child-Pugh-Turcotte and MELD score remain strong prognostic parameters and furthermore aid in identifying patients who fulfill criteria for liver transplantation. Such patients should be evaluated for early listing as potential candidates for transplantation and simultaneous hernia repair, especially in case of umbilical vein recanalization and uncontrolled refractory preoperative ascites. Considering surgical techniques, low-quality evidence suggests mesh implantation might reduce hernia recurrence without dramatically increasing morbidity, at least in elective circumstances. Preventing emergency surgery and optimizing perioperative care are crucial factors in reducing morbidity and mortality in patients with umbilical hernia and cirrhosis.

Laparoscopic Heated Intraperitoneal Chemotherapy in the Treatment of Carcinomatosis of Gastric Adenocarcinoma Origin.

The use of heated intraperitoneal chemotherapy (HIPEC) in conjunction with cytoreductive surgery has been gaining increasing traction in treating gastric adenocarcinoma with metastasis to the peritoneum in recent years. The addition of laparoscopic HIPEC (LS-HIPEC) to these treatment algorithms has increased the flexibility and adaptability of HIPEC integrating into treatment sequencing, allowing for iterative protocols of LS-HIPEC prior to cytoreduction as neoadjuvant treatment, as well as in the palliation of patients with unresectable disease and uncontrolled ascites. As the use of HIPEC in gastric adenocarcinoma continues to be refined, LS-HIPEC algorithms should continue to be considered and utilized both in curative treatment algorithms as well as in patients in the palliative setting. Given that LS-HIPEC remains a relatively nascent treatment modality, we advocate for its use in the setting of a clinical trial when feasible.

Controlled underdilation using novel VIATORR® controlled expansion stents improves survival after transjugular intrahepatic portosystemic shunt implantation

Background & AimsSmaller 8-mm diameter transjugular intrahepatic portosystemic shunts (TIPS) appear to be more beneficial than larger 10-mm TIPS stent-grafts, but lack the ability for secondary dilation in cases of clinical ineffectiveness. Underdilated VIATORR® TIPS stent grafts (VTS) expand passively, whereas novel VIATORR Controlled Expansion (VCX) stent grafts do not. This study evaluated the impact on survival of underdilated VCX compared with VTS in patients with decompensated cirrhosis.MethodsThis was a prospective case-control study including patients with cirrhosis receiving TIPS using 10-mm VCX underdilated to 8 mm. Patients with cirrhosis receiving 10-mm VTS underdilated to 8 mm were matched for age, sex, indication for TIPS, and liver function.ResultsA total of 114 patients (47 VCX, 47 VTS, and 20 fully dilated VCX/VTS) were included. After TIPS implantation, underdilated VCX diameter was 8.0 (7.8–9.2) mm at a median time of 359 (87–450) days, compared with VTS at 9.9 (9.7–10.0) mm (p <0.001). The portosystemic pressure gradient immediately after TIPS procedure and after 7 days did not change significantly in VCX [mean 9.4 (± 0.8) vs. 10.4 (± 0.7) mmHg, p = 0.115). Hospital readmission rates for hepatic encephalopathy were 23% (n = 11) vs 51% (n = 24) for VCX and VTS (p <0.001), respectively. Patients with VCX had significantly lower rates of large-volume paracentesis (n = 5 [11%] vs. n = 10 [21%], p = 0.017) and heart failure (n = 1 [2%] vs. n = 7 [15%], p = 0.015). One-year mortality for underdilated VCX and VTS was 15% (n = 7) and 30% (n = 14) and, for fully dilated VCX/VTS, was 45% (n = 9) (log-rank p = 0.008), respectively.ConclusionsThis study demonstrated that VCX stent grafts underdilated to 8 mm do not passively expand to nominal diameter and suggests reduced hospital readmissions because of hepatic encephalopathy, uncontrolled ascites, and heart failure, and improved 1-year survival compared with underdilated VTS.Lay summaryTransjugular intrahepatic portosystemic shunt (TIPS) improves survival in selected patients with liver cirrhosis and acute variceal bleeding or refractory ascites. Smaller 8-mm diameter TIPS stent grafts appear to improve patient outcome compared with larger 10-mm diameter stent grafts. Novel VIATORR® Controlled Expansion (VCX) stent grafts facilitate safe and stable underdilation to 8 mm of large 10-mm diameter stent grafts with improved patient outcome (survival, hepatic encephalopathy, ascites and heart failure) compared with legacy VIATORR TIPS stent graft (VTS). Thus, the use of underdilated VCX could preserve heart function.Clinical Trials RegistrationThe study is registered at Clinicaltrials.govNCT03628807.

Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites : a multicenter retrospective propensity score-matched cohort study

Background : The aim of this retrospective study was to determine whether tolvaptan treatment reduces the amount of albumin administered, volume of ascites removed, and frequency of paracentesis procedures in patients with decompensated cirrhosis with uncontrolled ascites with conventional diuretics. Patients and methods : The control (C) group included patients treated with conventional diuretics. The tolvaptan (T) group included patients treated with both tolvaptan and conventional diuretics. Both groups were matched according to baseline parameters. The amount of albumin administered, volume of ascites removed, and frequency of paracentesis within 30 days of onset of uncontrolled ascites were compared between the two groups. Results : After matching, 74 patients (C=37, T=37) were included. Baseline parameters (C vs. T group) were as follows : age, 69.5 ± 9.3 vs. 70.4 ± 11.0 years (p = 0.702) ; males, 24 (64.9%) vs. 25 (67.6%) (p = 0.999) ; patients with hepatocellular carcinoma, 17 (45.9%) vs. 18 (48.6%) (p = 0.999) ; serum albumin levels at treatment initiation, 2.76 ± 0.48 vs. 2.73 ± 0.49 g/dL (p = 0.773), and serum creatinine levels at treatment initiation, 1.18 ± 1.23 vs. 1.09 ± 0.48 g/dL (p = 0.679). In the C vs. T groups, respectively, mean amount of albumin administered was 51.0 ± 31.4 vs. 33.4 ± 29.8 g/month (p = 0.016) ; mean volume of ascites removed was 2,905 ± 4,921 vs. 1,824 ± 3,185 mL/month (p = 0.266) ; and mean frequency of paracentesis was 0.92 ± 1.46 vs. 0.89 ± 1.45 procedures (p = 0.937). Conclusions : Tolvaptan reduced the use of albumin infusion in patients with decompensated cirrhosis and was effective and acceptable for uncontrolled ascites.

Primary Amyloidosis

Abstract Introduction/Objective Amyloid light chain (AL) results from the deposition of immunoglobulin light chain fragments, and can lead to dysfunction in multiple organs. Our patient was being investigated for unknown malignancy with high differential for plasma cell neoplasm for severe amyloidosis leading to renal failure, uncontrolled ascites and thickening of the skin. The patient died of progressive liver and renal failure. Our autopsy findings show severe amyloidosis deposition in spleen, heart, kidney and liver with no significant plasma cells in the bone marrow, the findings correlate with a rare condition of primary AL amyloidosis. Methods 63 years old man with no past medical history presenting with progressive leg swelling with 15 pounds weight loss. He was admitted to another hospital a month ago. Patient was a smoker with a pack in 2-3 days for 38 years, occasional alcohol intake with no history of heavy alcohol use and no drug use. The patient worked as a chef and lived with his wife. Physical examination shows temporal wasting with cachecxia, had difficulty in staying upright and wanting to sleep when presented to the emergency department. Physical examination was significant for decreased breath sound bilaterally, more on left side, central weakness noted given difficultly sitting upright from laying down flat. Also, there were some lymphadenopathy in the jugular digastric region. Laboratory showed an increase elevation in alkaline phosphatase to the 1000s along with elevated LDL to 300s, nephrotic range proteinuria. Chest X-ray showed left pleural effusion and CT chest and abdomen showed slight hepatosplenomegaly with hypoattenuation and focal calcification. Autopsy finding indicated heavy spleen (260 grams) with a stiff and hard texture. Liver weighs in upper limit of normal (1660 grams) with a yellow firm surface. There is significant amyloid deposition in spleen. Also, moderate amyloid deposition was seen in all the organs including liver, kidney, heart and, also in the skin. No definite lesion was seen in the gross, nor cancer cells found in the microscopy examination. Bone marrow examination did not reveal plasma cells, ruling out the possibility of multiple myeloma or plasma cell dyscrasia. Conclusion This is a rare case of AL primary amyloidosis with aggressive progression and poor prognosis not associated with plasma cell neoplasm.

A Case of Uncontrolled Cancerous Ascites Reduced by Sekiganryo

A Case of Uncontrolled Cancerous Ascites Reduced by Sekiganryo

Regenerate: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Multicenter Study of Obeticholic Acid Therapy for Nonalcoholic Steatohepatitis

Introduction: Nonalcoholic Steatohepatitis (NASH) is a slowly progressive chronic liver disease without approved therapies. Patients with NASH and fibrosis are at high risk of increased mortality. Obeticholic Acid (OCA) is a selective and potent farnesoid X receptor (FXR) agonist, that has been shown to improve liver histology, including NAFLD activity score (NAS) and fibrosis, in a Phase 2 clinical trial (FLINT). Furthermore in FLINT, OCA treated patients had significant improvements in select liver biochemistries, markers of inflammation, and select cardiometabolic parameters. The ongoing, randomized, global, Phase 3 study REGENERATE, will further evaluate the effect of OCA on liver histology and clinical outcomes in patients with biopsy-confirmed NASH with stage 2-3 fibrosis. Methods: 2065 patients will be randomized 1:1:1 to 10 mg OCA, 25 mg OCA or placebo (Figure), each added to standard of care. An interim analysis at 18 months will evaluate the effect of OCA on liver histology. Total study duration is driven by time required to accrue a total of 264 outcome events and is estimated to be ˜6 years. Safety assessments will include adverse events (AEs), adjudicated cardiovascular events, and hepatic events as well as laboratory assessments. The effect of OCA on NASH and fibrosis severity will also be assessed by multiple noninvasive methods (FIB-4, APRI, transient elastography, magnetic resonance elastography, etc.).Figure 1Results: The co-primary liver histology endpoints at 18 months include: (I) improvement in fibrosis by ≥1 stage with no worsening of NASH and (II) resolution of NASH with no worsening in fibrosis stage. Further, confirmation of clinical benefit of OCA will be assessed at the end of the study by comparing the time to first occurrence of any of the following adjudicated events: histological progression to cirrhosis; uncontrolled ascites; hospitalization for: variceal bleed, hepatic encephalopathy or spontaneous bacterial peritonitis; hepatocellular carcinoma; liver transplant or eligibility for liver transplant (defined by model for end stage liver disease (MELD) score ≥15); and death. Conclusion: REGENERATE is the first pivotal study in NASH, designed in conjunction with FDA and meant to support approval of OCA for NASH with fibrosis. This robust Phase 3 study is designed to evaluate the effect of OCA on liver histology and effects on progression to cirrhosis, liver-related clinical outcomes and mortality.

The usefulness of C-reactive protein and neutrophil-to-lymphocyte ratio for predicting the outcome in hospitalized patients with liver cirrhosis

BackgroundThe role of clinical parameters such as systemic inflammatory response syndrome (SIRS) criteria in predicting the infection remains unclear in cirrhosis patients. The aim was to evaluate the usefulness of inflammatory markers including C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR) for diagnosis of infection and predicting the outcomes in hospitalized cirrhotic patients.MethodsThe study included 184 cirrhotic patients consecutively hospitalized from 2011 to 2012. The presence of overt infection and survival was evaluated. CRP concentration, NLR, Model for End-Stage Liver Disease (MELD) score and the presence of SIRS were assessed.ResultsThe main cause of admission was uncontrolled ascites (36.4 %), followed by varix bleeding (23.9 %), and hepatic encephalopathy (13.6 %). Fifty-eight patients (31.5 %) had overt infection during hospitalization and thirty-two patients (17.4 %) expired during the follow up period (median 38 months). Ninety-two patients (52.2 %) fulfilled the SIRS criteria and among them, only 32 patients (38.5 %) had the overt infection. For diagnose of the infection, baseline CRP concentration was a significant factor compared to the presence of SIRS (odds ratio 1.202, P = 0.003). For predicting one-month short-term survival, MELD score, NLR and WBC count were significant factors but in Child-Pugh class C patients, NLR was only an independent factor.ConclusionsCRP was a significant indicator of infection in hospitalized cirrhotic patients and a NLR was a useful predictor of 1-month survival, particularly in Child–Pugh class C patients. This study suggests that the inflammatory markers such as CRP and NLR can help identify cirrhotic patients at risk of unfavorable outcomes.

Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for (90)Y resin microspheres.

Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-((90)Y)-labeled resin microspheres. Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fisher's exact test and Kaplan-Meier estimates, respectively. Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade ≥3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2(nd)-line, 3(rd)-line, or 4(th)-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. ≥1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy. Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received ≥3 prior lines of chemotherapy.

Abstract CT415: A Phase I/IIA multicenter clinical trial of the chimeric monoclonal antibody NEO102 (NPC-1C) in adults with refractory pancreatic and colorectal cancer

Abstract Background:NPC-1C, (NEO-101 and NEO102, Precision Biologics, Inc) is a novel chimeric monoclonal antibody being developed as a treatment for pancreatic and colorectal cancers. NPC-1C recognizes a variant form of MUC5AC expressed specifically by human pancreatic and colorectal tumors. A Phase I trial of NEO-101 has been completed and reported previously. This Phase IIA study utilizes NEO-102, a glycoengineered form of NEO-101 with improved stability and decreased red cell agglutination. Methods: This is a Phase Ib/IIa, open label, multicenter dose escalation clinical trial with Neo-102 for patients with refractory pancreatic and colorectal cancer. The primary objective is to determine safety, tolerability of escalating doses of NEO-102. Secondary objectives are to assess pharmacokinetics as well as immune response at each dose level, evaluate clinical benefit as measured by RECIST criteria and overall survival, and to explore the immunologic correlates associated with NEO-102. Analyses of patient peripheral blood mononuclear cells (PBMCs) for antibody-dependent cell-mediated cytotoxicity (ADCC) and immune cytokine profiling utilizing the Milliplex MAP Human Cytokine/Chemokine Panel are planned to assess for immunologic outcome, and for correlation with clinical benefit. Patients with histologically confirmed adenocarcinoma of the pancreas who have progressed after front line chemotherapy; or metastatic colorectal cancer who have progressed after at least 2 chemotherapy regimens; whose tumors express the target NEO-102 antigen as defined as ≥ 20% positive stain by NPC-1C immunohistochemistry (IHC) are eligible. Patients have good performance status (KPS ≥ 50%) and adequate hematologic, hepatic and renal function are eligible. Major exclusion criteria include uncontrolled brain metastases, ascites, or other uncontrolled medical illness. Dose escalation was performed in a standard 3+3 design at doses of 1.5mg/kg, 2 mg/kg, 3 mg/kg and 4 mg/kg. Results: A total of 12 patients (2 pancreatic and 10 colon cancer) have been enrolled. Preplanned dose escalation to the 4 mg/kg dose has been completed and no dose limiting toxicity was observed. Median age is 58 years, 7 are male, median number of prior treatment regimens are 4+ (range 1+ to 8+) Treatment related AEs include grade 1 and 2 diarrhea, fatigue, mucositis, nausea, pruritus, epigastric pain, nasal congestion, insomnia, mouth ulcers, back pain, congestion, weight loss, chills facial flushing and fever, and grade 3 diarrhea and anemia. No severe adverse events (SAE) have been deemed to be drug related. Overall response rate includes 4 patients with PD and 5 patients have achieved SD and 3 patients are too early to evaluate. Median duration of treatment is 56+ days (Range 29 to131+). Conclusions: We have completed dose escalation with NEO-102, a first in man monoclonal antibody with a unique mechanism of action. Treatment is well tolerated with manageable safety profile. Due to encouraging preliminary clinical activity, as demonstrated by disease stabilization in a heavily pretreated population, a Phase II study of NEO-102 monotherapy in pancreatic and colon cancer is now enrolling patients. In addition, a combination study using NEO102 with cytotoxic chemotherapy in metastatic pancreatic cancer is underway. Citation Format: Muhammad Shaalan Beg, Michael Morse, Sandip P. Patel, Sharon Mavroukakis, Melony Beatson, Philip M. Arlen, Nilofer S. Azad. A Phase I/IIA multicenter clinical trial of the chimeric monoclonal antibody NEO102 (NPC-1C) in adults with refractory pancreatic and colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT415. doi:10.1158/1538-7445.AM2014-CT415

Early Diagnosis of Hepatic Hydrothorax with Associated Occlusion of a Peritoneo-Venous Shunt with Tc-99m MAA: Early Diagnosis of Hepatic Hydrothorax with Tc-99m MAA.

A 53-year-old man with pancreatic adenocarcinoma and status post subtotal pancreaticoduodenectomy was referred to evaluate patency of a peritoneovenous shunt (Denver shunt), which was placed for refractory ascites. The patient was injected with Tc-99m macroaggregated albumin (Tc-99m MAA) radiotracer, and immediate (30 min) and 4-h delayed scintigraphic images of the chest and abdomen obtained (Fig. 1a, b). Whereas a normal peritoneal scintigraphy would show radiotracer accumulation within the peritoneal cavity and further flow through the Denver shunt to the system circulation, in this case there was nonvisualization of the Denver shunt or cardiac and/or blood pool activities on both early and delayed images, suggesting obstruction of Denver shunt. Meanwhile, tracer uptake in the right hemithorax was observed on the 4-h delayed image, which led to suspicion for hepatic hydrothorax. Of note, at the time of the nuclear medicine study, there was only a minimal right-sided pleural effusion on a chest X-ray obtained 2 h earlier (Fig. 1c, arrows). Fig. 1 After the intraperitoneal injection of 5.2 mCi Tc-99m MAA, anterior images of the chest and abdomen were obtained at 30 min (a) and 4 h (b). A chest X-ray obtained after 2 h (c) The patient received a new Denver shunt replacement. However, a computed tomography (CT) scan of the chest obtained 2 weeks later demonstrated persistence of large ascites, and progression of hydrothorax into bilateral pleural spaces despite replacement of a new Denver shunt (Fig. 2a). In addition, portal venous thrombosis was also noted (Fig. 2b). Despite replacement, no significant improvement in the ascites was observed; thus, the severe hepatic hydrothorax likewise recurred and was classified as refractory hydrothorax. In past studies, the peritoneovenous shunt had been used successfully for recurrent hepatic hydrothorax and ascites, but in this instance, it was unsuccessful [1]. The patient had persist large amount ascites and worsening bilateral pleural effusions, which were refractory to various treatments including thoracentesis and paracentesis, and died from septic shock 2 months later. Fig. 2 CT of the chest obtained 2 weeks later demonstrated persistence of large ascites (a, dashed white arrow), and progression of hydrothorax into bilateral pleural spaces (a, block white arrows) despite replacement of a new Denver shunt (a, dashed ... Hepatic hydrothorax is the development of a pleural effusion in the setting of liver cirrhosis and portal hypertension, in the absence of cardiopulmonary disease [2]. Some cases have reported a hepatic hydrothorax without appreciable ascites [3, 4]. Although the exact mechanisms are not fully understood, hepatic hydrothorax probably results from the passage of ascites from the peritoneal cavity into the pleural cavity through small diaphragmatic defects [5, 6]. Though peritoneal scintigraphy with Tc-99m sulfur colloid can be used for detection of hepatic hydrothorax [7], our case demonstrated that Tc-99m MAA also can be used for this purpose, and was able to detect a minimal pleural effusion in the setting of severe uncontrolled ascites resulting from portal venous thrombosis. Though not as effective as replacing shunt, urokinase has been reported to be able to restore shunt patency [8]. Other treatment options for recurrent hydrothorax besides thoracentesis are transjugular intrahepatic portosystemic shunt (TIPS), pleurodesis, and thoracoscopic surgery to repair the diaphragmatic defect [9, 10].

Outcomes of Liver Transplantation, Partial Hepatectomy, and Transcatheter Arterial Embolization for Massive Polycystic Liver in Autosomal Dominant Polycystic Kidney Disease Patients.

Background: Polycystic liver disease(PLD) is the most common extra-renal manifestation in autosomal dominant polycystic kidney disease(ADPKD). Patients with PLD suffer from hepatomegaly leading to pain, dyspnea and caval obstruction. Interventions for symptomatic PLD include transcatheter arterial embolization(TAE), partial hepatic resection and liver transplantation(LT). We compared outcomes of each treatment modality. Methods: We retrospectively analyzed 29 patients who had undergone TAE, partial hepatectomy, or LT in ADPKD patients in a single center. Results: Six and seven patients underwent LT and partial hepatectomy, respectively, while sixteen patients underwent TAE. Living donor LT was performed for intractable hepatomegaly-related symptoms despite TAE in 2 patients, and for uncontrolled ascites in a patient. Deceased donor(DD) LT was performed in 2 patients for hepatic failure or uncontrolled ascites after TAE. Another patient underwent DDLT for hepatic failure after partial hepatectomy. The most common complications were ascites and pleural effusion. Two patients were under hemodialysis at LT, and acute kidney injury resulted in kidney failure in 1 DDLT patient. All patients had maintained good liver function at a median follow-up of 15.5 months, although subclinical acute cellular rejection was found in 2 patients. Causes of partial hepatectomy were recurrent cyst infection and hepatomegaly-related symptoms. One patient underwent partial hepatectomy, because multiple TAE had failed to control symptoms. Preoperative CTP score was lower in the partial hepatectomy group than in the LT group. A few serious infectious complications occurred, and antibiotic treatment cured them without mortality. Eleven patients received single TAE, and five patients underwent TAE twice. Two patients died of obstructive jaundice and cyst infection. Five patients (31.3%) in the TAE group needed LT or partial hepatectomy to relieve symptoms or rescue hepatic failure. Conclusion: LT is more effective and tolerable treatment option for symptomatic PLD in ADPKD patients compared to partial hepatectomy and TAE.

Treatment of decompensated cirrhosis secondary to hepatitis C with antiviral therapy.

To treat decompensated hepatitis C patient with interferon, ribavirin and amantidine to ascertain the sustained viral response. Descriptive study. Shifa International Hospital, Islamabad, from January 2007 to January 2012. HCV PCR patients with decompensated hepatitis C, who had developed a complication like ascites, encephalopathy or variceal bleeding were included in the study. Those with uncontrolled ascites or other complications were excluded. Treatment with standard interferon 3 miU subcutaneously three times a week along with ribavirin 800 mg to 1200 mg and amantidine 100 mg b.i.d. was administered for 12 months. Patients were followed every month with CBC and ALT and HCV PCR was performed after 3 months to document early viral response. They had HCV PCR at the end of the treatment to document end of treatment response. All were further followed for another 6 months at monthly intervals and HCV PCR was performed at the end of this period to document sustained viral response. In all, 165 patients were treated. Treatment had to be discontinued in 42 (26%) patients. Out of these, 16 patients died. Thus, 123 completed treatment. Sustained viral response was documented in 58 out of the 123 (47%) patients. Hepatic encephalopathy, gastrointestinal bleeding, sepsis and development of ascites were the major complications during treatment. Forty seven percent of patients with decompensated hepatitis C cirrhosis were able to achieve sustained viral response after one year treatment with anti-viral therapy. However, complications developed during treatment and, therefore, frequent and close monitoring is necessary in these patients.